tbuckley/cabot-search huggingface dataset:
Long-read sequencing reveals the landscape of aberrant alternative splicing and novel therapeutic target in colorectal cancer
Authors: Qiang Sun, Ye Han, Jianxing He, Jie Wang, Xuejie Ma, Qianqian Ning, Qing Zhao, Qian Jin, Lili Yang, Shuang Li, Yang Li, Qiaoming Zhi, Junnian Zheng, Dong Dong
Journal: Genome Medicine (2023)

Alternative splicing complexity plays a vital role in carcinogenesis and cancer progression. Improved understanding of novel splicing events and the underlying regulatory mechanisms may contribute new insights into developing new therapeutic strategies for colorectal cancer (CRC).Here, we combined long-read sequencing technology with short-read RNA-seq methods to investigate the transcriptome complexity in CRC. By using experiment assays, we explored the function of newly identified splicing isoform TIMP1 Δ4-5. Moreover, a CRISPR/dCasRx-based strategy to induce the TIMP1 exon 4-5 exclusion was introduced to inhibit neoplasm growth.A total of 90,703 transcripts were identified, of which > 62% were novel compared with current transcriptome annotations. These novel transcripts were more likely to be sample specific, expressed at relatively lower levels with more exons, and oncogenes displayed a characteristic to generate more transcripts in CRC. Clinical outcome data analysis showed that 1472 differentially expressed alternative splicing events (DEAS) were tightly associated with CRC patients' prognosis, and many novel isoforms were likely to be important determinants for patient survival. Among these, newly identified splicing isoform TIMP1 Δ4-5 was significantly downregulated in CRC. Further in vitro and in vivo assays demonstrated that ectopic expression of TIMP1 Δ4-5 significantly suppresses tumor cell growth and metastasis. Serine/arginine-rich splicing factor 1 (SRSF1) acts as a onco-splicing regulator through sustaining the inclusion of TIMP1 exon 4-5. Furthermore, CRISPR/dCasRx-based strategies designed to induce TIMP1 exon 4-5 exclusion have the potential to restrain the CRC growth.This data provides a rich resource for deeper studies of gastrointestinal malignancies. Newly identified splicing isoform TIMP1 Δ4-5 plays an important role in mediating CRC progression and may be a potential therapy target in CRC.
Single‐cell RNA sequencing of retina revealed novel transcriptional landscape in high myopia and underlying cell‐type‐specific mechanisms
Authors: Yunqian Yao, Zhenhua Chen, Qingfeng Wu, Yi Lu, Xingtao Zhou, Xiangjia Zhu
Journal: MedComm (2023)

High myopia is a leading cause of blindness worldwide with increasing prevalence. Retina percepts visual information and triggers myopia development, but the underlying etiology is not fully understood because of cellular heterogeneity. In this study, single-cell RNA sequencing analysis was performed on retinas of mouse highly myopic and control eyes to dissect the involvement of each cell type during high myopia progression. For highly myopic photoreceptors,
Arachidonic acid metabolism in health and disease
Authors: Yiran Zhang, Yingxiang Liu, Jin Sun, Wei Zhang, Zheng Guo, Qiong Ma
Journal: MedComm (2023)

Arachidonic acid (AA), an n-6 essential fatty acid, is a major component of mammalian cells and can be released by phospholipase A2. Accumulating evidence indicates that AA plays essential biochemical roles, as it is the direct precursor of bioactive lipid metabolites of eicosanoids such as prostaglandins, leukotrienes, and epoxyeicosatrienoic acid obtained from three distinct enzymatic metabolic pathways: the cyclooxygenase pathway, lipoxygenase pathway, and cytochrome P450 pathway. AA metabolism is involved not only in cell differentiation, tissue development, and organ function but also in the progression of diseases, such as hepatic fibrosis, neurodegeneration, obesity, diabetes, and cancers. These eicosanoids are generally considered proinflammatory molecules, as they can trigger oxidative stress and stimulate the immune response. Therefore, interventions in AA metabolic pathways are effective ways to manage inflammatory-related diseases in the clinic. Currently, inhibitors targeting enzymes related to AA metabolic pathways are an important area of drug discovery. Moreover, many advances have also been made in clinical studies of AA metabolic inhibitors in combination with chemotherapy and immunotherapy. Herein, we review the discovery of AA and focus on AA metabolism in relation to health and diseases. Furthermore, inhibitors targeting AA metabolism are summarized, and potential clinical applications are discussed.
Efficacy and safety of bemcentinib in patients with advanced myelodysplastic neoplasms or acute myeloid leukemia failing hypomethylating agents- the EMSCO phase II BERGAMO trial
Authors: A. S. Kubasch, P. Peterlin, T. Cluzeau, K. S. Götze, K. Sockel, R. Teipel, M. Jentzsch, H. Attalah, M. Sebert, F. Chermat, S. Gloaguen, M. Puttrich, M. Cross, M. Schneider, S. Kayser, D. Schipp, A. Giagounidis, I. Tirado-Gonzalez, A. Descot, A. van de Loosdrecht, A. Weigert, K. H. Metzeler, P. Fenaux, H. Medyouf, U. Platzbecker, L. Ades
Journal: Leukemia (2023)
A paracrine circuit of IL-1β/IL-1R1 between myeloid and tumor cells drives genotype-dependent glioblastoma progression
Authors: Zhihong Chen, Bruno Giotti, Milota Kaluzova, Montse Puigdelloses Vallcorba, Kavita Rawat, Gabrielle Price, Cameron J. Herting, Gonzalo Pinero, Simona Cristea, James L. Ross, James Ackley, Victor Maximov, Frank Szulzewsky, Wes Thomason, Mar Marquez-Ropero, Angelo Angione, Noah Nichols, Nadejda M. Tsankova, Franziska Michor, Dmitry M. Shayakhmetov, David H. Gutmann, Alexander M. Tsankov, Dolores Hambardzumyan
Journal: Journal of Clinical Investigation (2023)

Monocytes and monocyte-derived macrophages (MDMs) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here, we show that PDGFB-driven GBM cells induce the expression of the potent proinflammatory cytokine IL-1β in MDM, which engages IL-1R1 in tumor cells, activates the NF-κB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1β/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1β/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, and reduced exhausted CD8+ T cells and thereby extends the survival of tumor-bearing mice. In contrast to IL-1β, IL-1α exhibits antitumor effects. Genetic deletion of Il1a/b is associated with decreased recruitment of lymphoid cells and loss-of-interferon signaling in various immune populations and subsets of malignant cells and is associated with decreased survival time of PDGFB-driven tumor-bearing mice. In contrast to PDGFB-driven GBM, Nf1-silenced tumors have a constitutively active NF-κB pathway, which drives the expression of MCPs to recruit monocytes into tumors. These results indicate local antagonism of IL-1β could be considered as an effective therapy specifically for proneural GBM.
Reflux conditions induce E-cadherin cleavage and EMT via APE1 redox function in oesophageal adenocarcinoma
Authors: Heng Lu, Long Long Cao, Farah Ballout, Abbes Belkhiri, DunFa Peng, Lei Chen, Zheng Chen, Mohammed Soutto, Timothy C Wang, Jianwen Que, Silvia Giordano, Mary Kay Washington, Steven Chen, Oliver Gene McDonald, Alexander Zaika, Wael El-Rifai
Journal: Gut (2023)

Objective Chronic gastro-oesophageal reflux disease, where acidic bile salts (ABS) reflux into the oesophagus, is the leading risk factor for oesophageal adenocarcinoma (EAC). We investigated the role of ABS in promoting epithelial-mesenchymal transition (EMT) in EAC. Design RNA sequencing data and public databases were analysed for the EMT pathway enrichment and patients’ relapse-free survival. Cell models, pL2-IL1β transgenic mice, deidentified EAC patients’ derived xenografts (PDXs) and tissues were used to investigate EMT in EAC. Results Analysis of public databases and RNA-sequencing data demonstrated significant enrichment and activation of EMT signalling in EAC. ABS induced multiple characteristics of the EMT process, such as downregulation of E-cadherin, upregulation of vimentin and activation of ß-catenin signalling and EMT-transcription factors. These were associated with morphological changes and enhancement of cell migration and invasion capabilities. Mechanistically, ABS induced E-cadherin cleavage via an MMP14-dependent proteolytic cascade. Apurinic/apyrimidinic endonuclease (APE1), also known as redox factor 1, is an essential multifunctional protein. APE1 silencing, or its redox-specific inhibitor (E3330), downregulated MMP14 and abrogated the ABS-induced EMT. APE1 and MMP14 coexpression levels were inversely correlated with E-cadherin expression in human EAC tissues and the squamocolumnar junctions of the L2-IL1ß transgenic mouse model of EAC. EAC patients with APE1 high and EMT high signatures had worse relapse-free survival than those with low levels. In addition, treatment of PDXs with E3330 restrained EMT characteristics and suppressed tumour invasion. Conclusion Reflux conditions promote EMT via APE1 redox-dependent E-cadherin cleavage. APE1-redox function inhibitors can have a therapeutic role in EAC.
Treatable traits: a comprehensive precision medicine approach in interstitial lung disease, but why were acute exacerbations not considered?
Authors: Onofre Moran-Mendoza, Maria A. Coppola-Lamas, Elham Alrubai, Carla Paredes
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>It is suggested that acute exacerbations (AEs) should be recognised as a treatable trait and that the implementation of AE preventive measures should be included as a key component of a comprehensive care model in patients with interstitial lung disease</b>https://bit.ly/3r5xxiL
Synaptotagmin 1-triggered lipid signaling facilitates coupling of exo- and endocytosis
Authors: Svenja Bolz, Natalie Kaempf, Dmytro Puchkov, Michael Krauss, Giulia Russo, Tolga Soykan, Christopher Schmied, Martin Lehmann, Rainer Müller, Carsten Schultz, David Perrais, Tanja Maritzen, Volker Haucke
Journal: Neuron (2023)
Polymorphonuclear myeloid-derived suppressor cells and phosphatidylinositol-3 kinase gamma are critical to tobacco-mimicking oral carcinogenesis in mice
Authors: Khoa A Nguyen, Lisa N DePledge, Li Bian, Yao Ke, Von Samedi, Amber A Berning, Philip Owens, Xiao-Jing Wang, Christian D Young
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Oral squamous cell carcinoma (OSCC) is a devastating disease most often associated with tobacco consumption that induces a field of mutations from which a tumor arises. Identification of ways to prevent the emergence of cancer in high-risk patients is an ultimate goal for combatting all types of cancer, including OSCC. Methods Our study employs a mouse model of tongue carcinogenesis induced by tobacco carcinogen mimetic, 4-nitroquinoline 1-oxide (4NQO), to establish tongue dysplasia and OSCC. We use conventional histology, immunohistochemistry, multispectral imaging, mass cytometry, novel cell lines, pharmaceutical inhibition of PI3Kγ, T-cell suppression assays and mouse transplant models in our functional experimentation. Results In our study, we identify Ly6G+ granulocytes as the most abundant immune cell type in a model of tongue carcinogenesis induced by tobacco carcinogen mimetic 4NQO. Targeting Ly6G+ granulocytes with a pharmacologic inhibitor of PI3Kγ, an isoform of PI3K exclusively expressed by myeloid cells, resulted in reduced tongue dysplasia severity, and reduced rates of OSCC. Importantly, we performed functional assays with the Ly6G+ granulocytes induced in cell line models of 4NQO carcinogenesis to demonstrate that these granulocytes have increased polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) activity against T-cell proliferation and these PMN-MDSCs play a functional role in promoting tumor formation by inhibiting tumor regression in a PI3Kγ-dependent manner. Conclusions Overall, our data suggest that recruitment of PMN-MDSCs to sites of dysplasia is critical to immune suppression of CD8 T cells, thereby permitting malignancy, and PI3Kγ inhibitors are one mechanism to reduce PMN-MDSC recruitment, immunosuppression and tumorigenesis in OSCC.
Bispecific antibody CD73xEGFR more selectively inhibits the CD73/adenosine immune checkpoint on cancer cells and concurrently counteracts pro-oncogenic activities of CD73 and EGFR
Authors: Emily Maria Ploeg, Douwe Freerk Samplonius, Xiao Xiong, Xiurong Ke, Mark Alexander Johannes Martinus Hendriks, Isabel Britsch, Anne Paulien van Wijngaarden, Hao Zhang, Wijnand Helfrich
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background CD73 is an ecto-enzyme that is involved in the conversion of pro-inflammatory extracellular ATP (eATP) excreted by cancer cells under stress to anti-inflammatory adenosine (ADO). A broad variety of solid cancer types was shown to exploit CD73 overexpression as a suppressive immune checkpoint. Consequently, CD73-antagonistic antibodies, most notably oleclumab, are currently evaluated in several multicenter trials for clinical applicability. However, the efficacy of conventional monospecific CD73-inhibiting antibodies may be limited due to on-target/off-tumor binding to CD73 on normal cells. Therefore, a novel approach that more selectively directs CD73 immune checkpoint inhibition towards cancer cells is warranted. Methods To address this issue, we constructed a novel tetravalent bispecific antibody (bsAb), designated bsAb CD73xEGFR. Subsequently, the anticancer activities of bsAb CD73xEGFR were evaluated using in vitro and in vivo tumor models. Results In vitro treatment of various carcinoma cell types with bsAb CD73xEGFR potently inhibited the enzyme activity of CD73 (~71%) in an EGFR-directed manner. In this process, bsAb CD73xEGFR induced rapid internalization of antigen/antibody complexes, which resulted in a prolonged concurrent displacement of both CD73 and EGFR from the cancer cell surface. In addition, bsAb CD73xEGFR sensitized cancer to the cytotoxic activity of various chemotherapeutic agents and potently inhibited the proliferative/migratory capacity (~40%) of cancer cells. Unexpectedly, we uncovered that treatment of carcinoma cells with oleclumab appeared to enhance several pro-oncogenic features, including upregulation and phosphorylation of EGFR, tumor cell proliferation (~20%), and resistance towards cytotoxic agents and ionizing radiation (~39%). Importantly, in a tumor model using immunocompetent BALB/c mice inoculated with syngeneic CD73 pos /EGFR pos CT26 cancer cells, treatment with bsAb CD73xEGFR outperformed oleclumab (65% vs 31% tumor volume reduction). Compared with oleclumab, treatment with bsAb CD73xEGFR enhanced the intratumoral presence of CD8 pos T cells and M1 macrophages. Conclusions BsAb CD73xEGFR outperforms oleclumab as it inhibits the CD73/ADO immune checkpoint in an EGFR-directed manner and concurrently counteracts several oncogenic activities of EGFR and CD73. Therefore, bsAb CD73xEGFR may be of significant clinical potential for various forms of difficult-to-treat solid cancer types.
Mapping the landscape of immunonutrition and cancer research: a comprehensive bibliometric analysis on behalf of NutriOnc Research Group
Authors: Francesca De Felice, Carlo Guglielmo Cattaneo, Gianmario Edoardo Poto, Carmine Antropoli, Antonio Brillantino, Ludovico Carbone, Oronzo Brunetti, Raffaele De Luca, Isacco Desideri, Lorena Incorvaia, Roberta La Mendola, Federica Marmorino, Dario Parini, Maria Grazia Rodriquenz, Viola Salvestrini, Federica Sebastiani, Karol Polom, Luigi Marano
Journal: International Journal of Surgery (2023)

The ongoing global health challenge of cancer is driving the pursuit of innovative avenues for prevention, treatment, and enhanced outcomes. The convergence of nutrition and immune modulation, known as immunonutrition, is ready to act as a catalyst for transformative change in cancer research and therapy. Our study employs a bibliometric analysis to uncover the evolving trends within immunonutrition and cancer research across the past 25 years. Bibliometric data, including authors, journals, affiliations, and countries, were analyzed using the Bibliometrix R package. Clustering algorithms were applied to keywords to identify thematic areas and their evolution. A total of 489 documents were analyzed, showing an annual growth rate of 8.7%, with a collaboration index of 5.41, highlighting comprehensive multidisciplinary involvement within this landscape. Core authors demonstrated sustained productivity, while occasional authors indicated widespread interest. The Medical University of Warsaw led in institutional contributions. Country-wise, Italy, France, and the USA emerged as forerunners in fostering research productivity. Key journals like “Clinical Nutrition” served as beacons, emphasizing the multidimensional nature of this topic. The analysis highlighted growing research output and several collaborations, indicating the importance of immunoenriched nutrition in cancer treatment. The interplay of core authors and diversified engagement harmoniously accentuates the cross-disciplinary nature of this burgeoning field. International collaboration facilitated knowledge exchange. Prominent documents shaped the field, emphasizing the significance of nutritional interventions. Thematic clusters revealed varied focuses, including pharmaconutrients, surgical approaches, inflammation, and specific cancers. The expanding research output suggests further development, particularly in exploring immunoenriched nutrition’s impact on cancer types and patient populations. The multidisciplinary nature and international collaborations enhance the field’s progress. Gaps in research underscore the need for original studies and personalized approaches. This study guides future research, informing evidence-based nutritional interventions and advancing cancer care practices.
PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation
Authors: Srikanth Perike, Francisco J. Gonzalez-Gonzalez, Issam Abu-Taha, Frederick W. Damen, Laurin M. Hanft, Ken S. Lizama, Anahita Aboonabi, Andrielle E. Capote, Yuriana Aguilar-Sanchez, Benjamin Levin, Zhenbo Han, Arvind Sridhar, Jacob Grand, Jody Martin, Joseph G. Akar, Chad M. Warren, R. John Solaro, Sang-Ging Ong, Dawood Darbar, Kerry S. McDonald, Craig J. Goergen, Beata M. Wolska, Dobromir Dobrev, Xander H.T. Wehrens, Mark D. McCauley
Journal: Circulation Research (2023)

Atrial fibrillation (AF)-the most common sustained cardiac arrhythmia-increases thromboembolic stroke risk 5-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C (protein phosphatase 1 regulatory subunit 12C)-the PP1 (protein phosphatase 1) regulatory subunit targeting MLC2a (atrial myosin light chain 2)-causes hypophosphorylation of MLC2a and results in atrial hypocontractility.
Neutrophil membrane-engineered Panax ginseng root-derived exosomes loaded miRNA 182-5p targets NOX4/Drp-1/NLRP3 signal pathway to alleviate acute lung injury in sepsis: experimental studies
Authors: Chunhua Ma, Kun Liu, Fei Wang, Xiaochun Fei, Chaochao Niu, Tao Li, Liangming Liu
Journal: International Journal of Surgery (2023)

Background: The purpose of this study was to prepare neutrophil membrane engineered Panax ginseng root derived exosomes (N-exo) and investigate the effects of N-exo miRNA 182-5p (N-exo-miRNA 182-5p) on acute lung injury (ALI) in sepsis. Methods: Panax ginseng root derived exosomes were separated by differential centrifugation. Neutrophil membrane engineering was performed on exo to obtain N-exo. miRNA182-5p was transmitted into N-exo by electroporation technology to obtain N-exo-miRNA 182-5p. LPS was used to establish an in vivo and in vitro model of acute lung injury (ALI) in sepsis to evaluate the anti-inflammatory effect of N-exo-miRNA 182-5p. Results: The results of transmission electron microscope (TEM) showed that exo was a double-layer membrane structure like a saucer. Nanoparticle tracking analysis (NTA) particle size analysis showed that the average particle size of exo was 129.7 nm. Further, compared with exo, the level of miRNA182-5p was significantly increased in N-exo. The experimental results showed that N-exo-miRNA 182-5p significantly improved ALI via target regulation of NOX4/Drp-1/NLRP3 signal pathway in vivo and in vitro . Conclusion: In conclusion, this study prepared a novel engineered exosome (N-exo) and N-exo-miRNA 182-5p significantly improved ALI in sepsis via target regulation of NOX4/Drp-1/NLRP3 signal pathway, providing new ideas and methods for treatment of ALI in sepsis.
Hypothermic oxygenated perfusion in liver transplantation: a meta-analysis of randomized controlled trials and matched studies
Authors: Gang Tang, Linyu Zhang, Lingying Xia, Jie Zhang, Zhengqiang Wei, Rongxing Zhou
Journal: International Journal of Surgery (2023)

Background: Hypothermic Oxygenated Machine Perfusion (HOPE) is a novel organ-preservation technology designed to optimize organ quality. However, the effects of HOPE on morbidity and mortality after liver transplantation remain unclear. This meta-analysis evaluated the potential benefits of HOPE in liver transplantation. Materials and methods: The Embase, Web of Science, PubMed, Cochrane Library, and Scopus databases were searched for articles published up to June 15, 2023 (updated on August 12, 2023). Mean differences (MD), risk ratios (RR), and 95% confidence intervals were calculated. Results: Eleven studies encompassing five randomized controlled trials and six matched studies were included, with a total of 1000 patients. HOPE did not reduce the incidence of major postoperative complications (RR 0.80), primary nonfunction (PNF) (RR 0.54), reperfusion syndrome (RR 0.92), hepatic artery thrombosis (RR 0.92), renal replacement therapy (RR 0.98), length of hospital stay (MD, −1.38 d), 1-year recipient death (RR 0.67), or intensive care unit stay (MD, 0.19 d) after liver transplantation. HOPE reduced the incidence of biliary complications (RR 0.74), non-anastomotic biliary strictures (NAS) (RR 0.34), early allograft dysfunction (EAD) (RR 0.54), and acute rejection (RR 0.54). In addition, HOPE improved the retransplantation (RR 0.42) and 1-year graft loss rates (RR 0.38). Conclusions: Compared with static cold storage (SCS), HOPE can reduce the incidence of biliary complications, NAS, EAD, and acute rejection and retransplantation rate after liver transplantation and improve the 1-year graft loss rate. These findings suggest that HOPE, when compared to SCS, can contribute to minimizing complications and enhancing graft survival in liver transplantation. Further research is needed to investigate long-term outcomes and confirm the promising advantages of HOPE in liver transplantation settings.
A commentary on ‘Nomogram of conditional survival probability of long-term survival for metastatic colorectal cancer: a real-world data retrospective cohort study from SEER database’
Authors: Cong Liu, Yingying Lv, Xiaofeng Li, Yufeng Wang, Feng Guo
Journal: International Journal of Surgery (2023)

Liu, Cong MM; Lv, Yingying MM; Li, Xiaofeng MD; Wang, Yufeng MM; Guo, Feng MD Author Information